FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
"NEW METHODS FOR THE PREPARATION OF DULOXETINE HYDROCHLORIDE AND INTERMEDIATES THEREOF"
2. APPLICANT (S)
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: B- Wing, 10th Floor, BSEL Tech Park, Sector 30 A,
Plot no.39/5 & 39/5A, Opp. Vashi Railway Station, Navi Mumbai- 400 703, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the invention
The present invention relates to improved synthetic processes for the preparation of Duloxetine hydrochloride of Formula (I) or its pharmaceutically acceptable salts and its intermediates thereof

Background and prior art
Duloxetine hydrochloride marketed as CYMBALTA in USA is a serotonin-norepinephrine reuptake inhibitor (SNRI) used for major depressive disorder (MDD), generalized anxiety disorder (GAD), pain related to diabetic neuropathy and fibromyalgia and in some countries for stress urinary incontinence (SUI).
Duloxetine hydrochloride is chemically known as (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride represented by the formula (I) Duloxetine was first disclosed in US Patent No. 4956388. The said patent discloses the preparation of duloxetine wherein, a mixture of 2-acetylthiophene, dimethylamine hydrochloride, paraformaldehyde and hydrochloric acid in ethanol are heated together to obtain 3-Dimethylamino-l-(2-thienyl)-1-propanone hydrochloride which was reduced to give α-[2-(Dimethylamino) ethyl]-2-thiophene methanol with NaBH4 in methanol. Sodium hydride in dimethylacetamide was then added followed by treatment with 1-fluoronaphthalene to yield N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine. The final product is crystallized as its oxalate salt.
Deeter, et al., in Tetrahedron Letters, 31(49), 7101—04 (1990) discloses the synthesis of Duloxetine starting from acetyl thiophene.
WO2007/105021 discloses fumarate, citrate or mandelate salts of (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thiophenyl)propanamine.

There are many patents describing the preparation of duloxetine which can be depicted by the general scheme I;

US5362886 provides a process for the preparation of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine(III), by dissolving (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine(II) with sodium hydride in dimethylsulfoxide (DMSO) and reacting with 1- fluoronaphthalene followed by conversion to phosphoric acid salt. The product obtained is further converted to Duloxetine phenyl carbamate by reacting with phenylchloroformate, which is further reacted with sodium hydroxide in dimethylsulfoxide (DMSO) to form Duloxetine followed by reacting with HCl to form Duloxetine HCl.
US5641668 claims a process of reacting (S)-(-)-N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1-fluoronaphthalene in the presence of N-Methyl pyrrolidine as a solvent at a temperature of 140°C. The publication also discloses employment of potassium tert. butoxide as the base for the condensation reaction.
PCT application WO2006/126213 discloses the reaction of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1-fluoronaphthalene in the presence of solvents such as dimethylsulfoxide, dimethylformamide and dimethylacetamide and organic alkoxide as a base.
US20070238883 describes the reaction of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1-fluoronaphthalene in the presence of a base selected from a group comprised of metal alkoxide, alkaline earth oxides and a polar organic solvent.
US2008293952 describes a method of preparation of (S)-N-methyl-3-(l-naphthyloxy)-3-(2-mienyl)propylamine (formula l)and its pharmaceutically acceptable salts, comprising

(a)reacting (RS)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine with optically active D-tartaric acid or an acid salt derived from D-tartaric acid forming a mixture of diastereoisomeric salts of N,N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine and D-tartaric acid (2:1) (b) isolating the salt (S)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate (2:1) from the mixture of diastereoisomeric salts in an organic solvent, water or a mixture thereof and release of (S)-N,N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine by action of an inorganic or organic base (c) demethylation of (S)-N,N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine by action of an alkylchloroformate of formula ClCOOR (R=C1-C5 alkyl, or C6-C12 aryl or alkylaryl), especially phenyl, ethyl or methyl chloroformate, and d) hydrolytic release of the duloxetine base of formula I and optionally conversion of the base to a salt with the respective acid, or salt of a weak base.
The methods described in the prior art for condensation of racemic or enantiomeric hydroxy compound with 1-fluoronaphthalene suffers from the following drawbacks:
a) The condensation process is conducted in presence of a base such as sodium hydride or alkoxide. The alkoxides are very strong bases which are hazardous and hence not industrially viable. Sodium hydride being pyrophoric reacts violently with water. This limits the use of sodium hydride on the industrial scale. Further, sodium fluoride generated is highly toxic and makes the process incompatible.
b) The use of polar solvents such as DMSO, DMAC are not suitable commercially as they are not easily recoverable, are expensive, also removal of these solvents is difficult as they undergo decomposition at high temperature leading to its presence in trace amounts in the final API. Additionally DMSO is an oxidizing agent at temperatures of more than 80°C because of which arylation reduction rate gets reduced (WO 2009 0748883).
c) The dimethyl anion generated in the reaction of S-isomer in presence of DMSO and sodium hydride as a base results in racemization and formation of R-isomer in the final product thus leading to impurity formation affecting the yield and purity of the product.

d) The processes of the prior art employs costly and also potentially
hazardous reagents, requires special skills to handle and are difficult to
carry out on industrial scale.
There is, therefore a need for an improved process for the preparation of Duloxetine that
is easy to scale up as well as avoids the use of fluoro compounds, potentially hazardous
solvents, bases etc thus overcoming the disadvantages of the processes in the prior art.
Thus the inventors have developed alternate processes which involve a catalytic route for the preparation of duloxetine, which is safe, easy to operate on industrial scale.
Object of the invention
The main object of the invention is to provide a novel catalytic route for preparation of duloxetine or its pharmaceutically acceptable salts in good yield and purity and which involves fewer steps, avoids the use of hazardous reagents thus providing for industrial scalability.
The other object of the invention is to provide alternate routes for the preparation of (S)-(-)-N-methyl-3-(2-thienyl)-3-hydroxypropanamine and employing the same for the preparation of Duloxetine.
Summary of the invention
In view of the above-mentioned complexities, the inventors have conducted various studies with the aim of achieving the above-mentioned object.
In a preferred aspect, the present invention relates to Heck's coupling of 2-bromo thiophene with an alkene Heck acceptor; such as N-acetyl-N-methyl acrylamide, or N-methyl-allyl amine or N-methyl acrylamide, in presence of a base and palladium metal catalyst, to obtain intermediates of Formula iV, Formula V, and Formula VI;


The intermediate IV is then subjected to Michael addition of 1-naphthol in presence of a catalyst to obtain Michael addition product of Formula VII, which is hydrolyzed in presence of a base followed by reduction with NaBH4 to yield racemic duloxetine.

The intermediate V as obtained above may be subjected to hydration to obtain compound IX and further resolving the said compound IX by employing L-(+) tartaric acid to obtain compound X. The compound X can be further reacted with 1-naphthol in presence of acid catalyst (eg. trifluoroacetic acid) to yield duloxetine.

Intermediate of Formula V is reduced catalyticaily to compound of Formula VIII which is then subjected to benzylic hydroxylation to obtain the precursor for O-arylation (compound of formula IX) with 1-naphthol to yield racemic duloxetine.

Alternately, intermediate of formula V can be acylated using suitable acylating agent to yield the amide of formula XII;


followed by reaction (SNi) of 1-naphthol in presence of acid and a hydrocarbon solvent to yield compound of formula XIII, which on basic hydrolysis yields racemic duloxetine.

In another preferred aspect, the present invention provides a process comprising addition of Mannich adduct (formed by reaction between formaldehyde and monomethylaminehydrochloride) to 2-vinyl thiophene in Prins fashion, in presence of lower alcohols as a solvent, followed by addition of 1-naphthol resulting in the formation of racemic duloxetine.
Racemic duloxetine obtained from Heck's coupling and Prins reaction as described above is resolved to enantiomerically pure duloxetine by employing L(+)-tartaric acid.
In yet another preferred aspect, the present invention provides a Mannich reaction comprising reacting monomethylamine tartrate salt with paraformaldehyde and 2-acetyl thiophene to obtain β-amino ketone followed by asymmetric reduction of the tartaric acid Mannich adduct with alkali metal borohydride, preferably sodium borohydride. The product obtained (Formula XIV) is reacted with 1-naphthol to obtain duloxetine.

The process according to the present invention provides a novel intermediate of Formula IV;

Also disclosed is a novel intermediate of Formula VII;



Disclosed herein is intermediate of Formula V,

Further disclosed herein is the novel intermediate of Formula XII;

Also disclosed herein is the intermediate of Formula XJII;

The process of the present invention is described herein after in more details substantiating various embodiments and conditions of reaction for better understanding/appreciation of the invention.
Detailed description of the invention
Included in the scope of the invention is a catalytic process for the preparation of duloxetine of Formula I or its pharmaceutically acceptable salt;


which comprises reacting 2-substituted thiophene as given below;

wherein, R is selected from alkylene, halo, acetyl or vinyl, with Heck alkene acceptor such as suitably substituted amide or N-substituted allyl amine or N-methyl acrylamide which is optionally hydrated or acetylated and further subjected to Michael addition of 1-naphthol or alternately with Mannich adduct in Prins fashion.
Accordingly, in an embodiment, the present invention relates to a process for carbon-carbon coupling reaction between heteroaryl halide, and olefin using heterogeneous palladium (Pd) catalyst to produce the corresponding heteroaryl-olefin compounds as intermediates useful for preparation of duloxetine or its pharmaceutically acceptable salts.
In particular, the present invention provides Heck coupling reaction of 2-bromo thiophene with an alkene Heck acceptor; N-acetyl-N-methyl acrylamide, in presence of a base and palladium metal catalyst to obtain intermediate of Formula IV,

The intermediate (IV) is then subjected to Michael addition of 1-naphthol in presence of a catalyst to obtain condensation product of Formula VII;


The compound (VII) is then refluxed with sodium acetate to obtain compound of formula XI. Carbonyl reduction of compound XI with alkali metal borohydride yields racemic duloxetine.
In another embodiment, the Heck coupling reaction comprises reacting 2-bromo thiophene with an alkene Heck acceptor, N-methyl-allyl amine and N-methyl-acrylamide in presence of a base and palladium catalyst to obtain intermediates of Formula V and Formula VI;
Intermediate of Formula V is reduced catalytically to compound of Formula VIII which is then subjected to benzylic hydroxylation to obtain the precursor for O-arylation (compound of formula IX) with 1-naphthol to yield racemic duloxetine.

The intermediate V as obtained above may be subjected to hydration in presence of acid to obtain compound IX and further resolving the said compound IX by employing L-(+) tartaric acid to obtain compound X. The compound X can be further reacted with 1-naphthol in presence of a catalyst such as trifluoroacetic acid, to yield duloxetine.
Alternately, intermediate of formula V can be acylated using suitable acylating agent to yield the amide of formula XII,

which is then subjected to Michael addition of 1-naphthol in trifluoroacetic and a hydrocarbon solvent to yield compound of formula XIII,


The compound of formula XIII is then subjected to base hydrolysis to yield racemic duloxetine.
The palladium catalyst employed in the Heck's coupling reaction is selected from palladium acetate, palladium chloride dipalladium tris (dibenzylidenelacetone) ("PdDBA"), palladium tetrakistriphenylphosphine and the like. The palladium catalysts are commercially available, and methods for preparing such palladium catalysts are known to those skilled in the art.
Useful bases used for Heck's coupling reaction include, but are not limited to, alkali metal carbonates, alkali metal hydroxides, and mixtures thereof Suitable alkali metal carbonates include, but are not limited to, potassium carbonate, sodium carbonate, and the like. Suitable alkali metal hydroxides include, but are not limited to, potassium hydroxides, sodium hydroxides and the like.
If desired, the Heck's coupling reaction can be conducted in water or a solvent. Useful solvents include, but are not limited to, polar solvents such as 1,4-dioxane, methanol, ethanol or non-polar solvents such as benzene, toluene, and the like and mixtures thereof.
Further, the Heck coupling reaction is preferably conducted at reflux temperature of the solvent used. The reaction is allowed to proceed, preferably with stirring for a sufficient period of time, e.g., a time period ranging from about 10 to about 24 hours.
After completion of reaction, the intermediates formed are isolated by conventional procedures such as filtration or separation of layers by addition of water and polar aprotic solvents followed by concentration of the organic layer under pressure.
The catalyst used for Michael addition is selected from metallic copper or copper compound such as Cu2O, CuCl, CuCN, copper acetylacetonate, copper (II)

tetrafluoroborate etc. in polar solvents such as lower alcohols, ethyl acetate, methylene dichloride, acetone, etc. The reaction is carried out at ambient temperature for 10-13 hours.
The catalyst used for the reduction of compound of formula VII may be selected from Pt, Pd/C, raney nickel etc. The reduction is carried out under hydrogen pressure for about six hours. Benzylic hydroxylation is carried out using selective oxidants such as manganese dioxide, hydrogen peroxide in presence of a catalyst, titanium dioxide, vanadium pentoxide etc. preferably vanadium pentoxide.
The following scheme illustrates the formation of the intermediates formed by Heck's coupling which are useful for preparation of duloxetinel

Thus in one of the preferred embodiment, the process of the present invention includes the Heck coupling of N-acetyl-N-methylacrylamide with 2-bromo thiophene dissolved in a mixture of methanol and toluene, in presence of palladium (II) acetate and sodium carbonate at reflux temperature for about 10-14 hrs to obtain compound of Formula IV. The compound of formula IV dissolved in ethyl acetate is further subjected to Michael addition of 1-naphthol in presence of Cu(I) to obtain compound of formula VII which on refluxing with aqueous sodium acetate yields compound XI. Subsequent carbonyl reduction of compound XI with sodium borohydride yields racemic duloxetine. The process is schematically shown below;


In another preferred embodiment, the Heck coupling includes the steps of reacting 2-bromothiophene dissolved in a mixture of methanol and toluene with N-methyl-allylamine in presence of palladium (II) acetate and sodium carbonate at reflux temperature for about 10-14hrs to obtain compound of Formula V. The intermediate (V) is isolated by filtration followed by extraction in ethyl acetate.
In one of the embodiment, Intermediate V is hydrated in presence of acid catalyst to give compound IX which is further resolved using L(+) tartaric acid to enantiomer X. Compound X is then O-arylated with 1 - naphthol in presence of a catalyst to yield duloxetine.
In an alternate embodiment, compound of formula IX may be prepared from intermediate V. Accordingly intermediate V is reduced with Pd/C under hydrogen pressure to give compound of formula VIII which is further subjected to benzylic hydroxylation with vanadium pentoxide at room temperature for 12 hours. Compound IX is further resolved using L(+) tartaric acid to enantiomer X. Compound X is then 0-aryIated with I-naphthol in presence of a catalyst to yield duloxetine.
The process is schematically shown below:


Alternately, the compound of formula V may be acetylated with acetyl chloride at room temperature to obtain compound of Formula XII followed by Michael addition of 1-naphthol in presence of trifluoroacetic acid to yield compound of formula XIII. The resultant mixture is then quenched with 25% NaOH solution to yield racemic duloxetine. The process is schematically represented below;

In yet another preferred embodiment, the present invention provides a process comprising addition of Mannich adduct to 2-vinyl thiophene in Prins fashion, in presence of lower alcohols, followed by addition of 1-naphthol resulting in the formation of racemic duloxetine.
The Mannich adduct is formed from methylamine hydrochloride and paraformaldehyde. 2-vinyl thiophene is obtained by dehydration of thiophene-2-ethanol using aq. HCl at a temperature of 45-50°C.
The process is depicted in the scheme below:


Thus according to the preferred embodiment, thiophene-2-ethanol is dehydrated in presence of aq. HCl at a temperature of 45-50°C to obtain vinyl thiophene. The crude olefin is then heated with the Mannich adduct, formed from methylamine hydrochloride and paraformaldehyde, in presence of l-naphthol to reflux to yield racemic duloxetine which is further converted to its hydrochloride salt by passing HCl gas.
In an embodiment, racemic duloxetine obtained from Heck's coupling and Prins reaction as described above is resolved to obtain enantiomerically pure duloxetine using resolving chirai acids known in the prior art, preferably L(+)-tartaric acid. The solvents employed for the optical resolution is selected from lower alcohols such as methanol, ethanol, propanol, isopropanol;. The most preferred solvent for the resolution is methanol.
The resolution is carried out at the reflux temperature of the solvent used and then allowing cooling the reaction mixture followed by adjusting the pH of the reaction mixture with a base. The solid obtained is filtered and washed with an aliphatic C1-C7 hydrocarbon solvent to obtain the desired enantiomer with optical purity of 99%.
In still another preferred embodiment, the present invention provides a Mannich reaction comprising reacting monomethylamine tartrate salt with paraformaldehyde and 2-acetyl thiophene to obtain p- amino ketone followed by asymmetric reduction of the tartaric acid mannich adduct with alkali metal borohydride, preferably sodium borohydride as shown in scheme below;


The product obtained (Formula XIV) is reacted with 1-naphthol to obtain duloxetine.
The process according to the present invention provides a novel intermediate of Formula
IV;

Also disclosed is a novel intermediate of Formula VII;

Disclosed herein is intermediate of Formula V,

Further disclosed herein is the novel intermediate of Formula XII;


Also disclosed herein is the intermediate of Formula XIII;

The advantage of the present invention is found in its ability to obtain the desired enantiomeric product in comparable yield and purity with optical purity of 99%, employing novel coupling processes which enable to achieve the desired functionality. Further, the intermediates so formed by the coupling processes easily undergo Michael addition of !-naphthol followed by basic hydrolysis and resolution to obtain desired enantiomer S-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine in comparable yield and purity. Thus the process is industrially viable as it avoids the use of hazardous solvents, utilizing reduced number of steps, and avoids impurity formation.
Further details of the process of the present invention will be apparent from the examples presented below. Examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.
Example 1: Preparation of 2-vinylthiophene
25.0 grams of thiophene-2-ethanol was charged into 25.0 ml 10 N aq. HCl solution. The reaction mixture was heated at a temperature of 45 -50°C for 4 hours. The reaction mixture was cooled and extracted with toluene (25.0 * 3 ml). The toluene layer was concentrated under reduced pressure to obtain 18.0 grams of the crude product. The crude olefin obtained was subjected to further reactions.
Example 2: Preparation of racemic Duloxetine hydrochloride starting from 2-vinyl thiophene
25.0 grams of 2-vinyl thiophene was dissolved in 50.0 ml of methanol. 4.4 grams of paraformaldehyde was charged followed by 32.0 grams of 1-naphthol and 7.0 grams of the Monomethylamine hydrochloride. The resultant mixture was heated to reflux for 8 hours. The resultant mixture was concentrated under reduced pressure. The thick mass

obtained was dissolved in methylene dichloride and the resultant solution was cooled to 0 -5°C. The HCl gas was purged into the solution until the solution turned sufficiently acidic. A white colored soJid separated which was filtered and dried. The product weighed 34 grams (50 % yield, 99 % purity).
Example 3: Resolution of racemic Duloxetine
25.0 grams of duloxetine hydrochloride obtained from example -2 was dissolved in 50 ml Methanol. The solution was cooled and the pH adjusted to 4.5. The resultant mixture was cooled to obtain a solid. The solid was filtered out. The solid was then dissolved in methanol and heated with 13.0 grams of L-(+)-Tartaric acid to reflux. The resultant mixture was cooled and the solid obtained was filtered out. The solid was dissolved in 20.0 ml acetic acid and the complex was broken by employing triethylamine by adjusting the pH to 4.0. The solid obtained was filtered, washed with 50 ml Hexane (25.0 * 2) and dried. The product (S-enantiomer) weighed 10.0 grams, 99 % e.e, 80 % yield.
Example 4: Preparation of compound of Formula IV:
25.0 grams of 2-bromothiophene was dissolved in 50 ml methanol. 25.0 ml Toluene was added to the above reaction mixture. 2.0 grams palladium (II) acetate was added followed by 5.0 grams of sodium carbonate and 20.0 grams of N-acetyl-N-methyl-acrylamide. The resultant mixture was refluxed for 14 hours. 50.0 ml water was added and the organic layer was separated. The organic layer was concentrated under reduced pressure to obtain compound of Formula -IV, 24.0 grams, 75 % yield.
Example 5: Preparation of compound of Formula XI:
20.0 grams of compound of Formula - IV was dissolved in ethylacetate. 500 mg of Cu(l) was added followed by 13.8 grams of I-naphthol. The resultant mixture was heated for 12 hours. After refluxing for 12 hours, the reaction mixture was concentrated under reduced pressure. The solid obtained (compound of formula VII) was dissolved in water and the resultant solution was refiuxed with 10.0 grams of sodium acetate. The reaction mixture was cooled and extracted with 50.0 ml methylene dichloride(MDC). The MDC solution was concentrated to obtain the white colored amide, 20.0 grams, 98 % purity.

Example 6: NaBH4 reduction of the compound of formula XI
20.0 grams of the compound of Formula XI was dissolved in 50.0 ml methanol and 1.0 gram of NaBH4 was added portion wise. The resultant mixture was allowed to stir for 4 hours. The reaction mixture was quenched with 1 N HCl followed by extraction with 50.0 ml ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure to yield racemic duloxetine, 14.5 grams, 70 % yield.
Example 7: Preparation of compound of Formula -V
20.0 grams of 2- bromo thiophene was dissolved in 40.0 ml methanol and 10.0 ml toulene. 10.0 grams of sodium bicarbonate was added and the resultant mixture was stirred for 30.0 minutes. 10.0 grams of N-methyl-allyl-amine was then added and the resultant mixture was refluxed for 12 hours in the presence of palladium (II) acetate. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure. The concentrated mass was then dissolved in water and extracted with 50.0 mi ethyl acetate. The ethyl acetate layer was concentrated under pressure to obtain the compound of formula -V, 15.0 grams, 75 % yield.
Example 8: Preparation of compound of Formula -VIII
25.0 grams of compound of Formula V was dissolved in 40.0 ml ethanol. 1.0 gram Pd/C was added and the resultant mixture was stirred under hydrogen pressure for 6 hours. The resultant mixture was filtered. The filtrate was concentrated under reduced pressure. The residue obtained was dissolved in MDC and washed with water (25.0 ml). The MDC layer was concentrated under reduced pressure to obtain the product, 21.5 grams, 85 % yield.
Example 9: Preparation of compound of Formula -IX.
25.0 grams of compound of Formula VIll was dissolved in methanol.2.5 grams vanadium pentoxide was added and the resultant mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 18.0 grams of the product (80 % yield).
Example 10: Preparation of the compound of Formula-XIV:
15.0 grams of Tartaric acid was dissolved in 25.0 ml methanol. Methylamine was bubbled in to the solution to obtain the methylamine tartaric acid salt. The salt obtained was

filtered. 16.0 grams of the salt was dissolved into 50 ml methanol followed by the addition of 2.85 grams of paraformaldehyde and the resultant mixture was heated for 12 hours. The reaction mass concentrated under reduced pressure and washed with methanol to obtain the compound of formula XIV, 11.4 grams (70 % yield).
Example 11: Preparation of the compound of Formula - XII
25.0 grams of the compound of Formula V was dissolved in 50.0 ml ethylacetate. 12.8 grams of acetyl chloride was added and the resultant mixture was allowed to stir for 6 hours. The ethyl acetate layer was washed with 25.0 ml water and concentrated under reduced pressure to obtain the compound of Formula XII, 22.0 grams (70 % yield).
Example 12: Preparation of the compound of Formula XIII:
25.0grams of the compound of Formula XII was dissolved in 25.0 ml of trifluoroacetic acid. 18.4 grams of 1-naphthol was added and the resultant mixture was stirred for 6 hours. The reaction mixture was quenched with 25 % NaOH solution and allowed to stir for 2 hours. The resultant reaction mixture was extracted with 50.0 ml ethyl acetate. The ethyl acetate layer was washed with water and concentrated under reduced pressure to obtain compound of Formula XIII, 30.0 grams (70 % yield).
Example 13: Preparation of Duloxetine from compound of Formula - XIII
25.0 grams of the compound of Formula XIII was dissolved in 25.0 ml methanol and 25.0 ml water. 6.0 grams of NaOH was added and the resultant mixture was stirred for 6 hours. The reaction mass was quenched with acetic acid and extracted into 50 ml MDC. The MDC layer was purged with anhydrous HCl. The solid obtained was filtered and dried. 17.5 grams of Duloxetine hydrochloride was obtained (70 % yield).
Example 14: Hydration of compound of Formula-V
25.0 grams of the compound of Formula V was dissolved in 125.0 ml THF and 10.0 ml water. 1.0 ml H2SO4 was added and the reaction mixture was refluxed for 22 hours. The reaction mixture was concentrated and extracted into 50.0 ml MDC. The MDC solution was washed with water (25.0 *3). The MDC solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (Formula IX), 16.7 grams (60 %), purity = 95 %.

We Claim,
1. A novel process for preparation of duloxetine or its pharmaceutically
acceptable salts which comprises the steps of;
(a) reacting 2-substituted thiophene as given below;

wherein, R is selected from alkylene, halo, acetyl or vinyl, with Heck alkene acceptor such as suitably substituted amide or N-substituted allyl amine or N-methyl acrylamide, in presence of a base and a catalyst, which is optionally hydrated or acetylated, and further subjected to Michael addition of l-naphthol;
(b) hydrolyzing the Michael adduct formed in step (a) with a base and optionally reduced to obtain racemic duloxetine; and
(c) resolving racemic duloxetine with L (+) tartaric acid.
2. The process as claimed in claim 1, wherein preparation of duloxetine or its
pharmaceutically acceptable salts comprises the steps of;
(a) Heck's coupling of 2-bromo thiophene with N-acetyl-N methyl acrylamide in presence of a base and a catalyst followed by Michael addition of l-naphthol to obtain compound VII;
(b) Hydrolyzing compound VII in presence of base followed by reduction of carbonyl group to obtain racemic duloxetine; and
(c) Resolving racemic duloxetine with L (+) tartaric acid.
3. The process as claimed in claim 1, wherein preparation of duloxetine or its
pharmaceutically acceptable salts comprises the steps of;
(a) Heck's coupling of 2-bromo thiophene with N-methyl allyl amine in presence of a base and a catalyst to obtain intermediate V which is subjected to hydration in presence of acid or optionally reduced and hydroxylated to yield compound IX;
(b) Resolving compound IX with L (+) tartaric acid to give compound X;
(c) O-arylating compound X in presence of catalyst such as trifluoroacetic acid with l-naphthol to yield duloxetine.

4. The process as claimed in claim 3, wherein preparation of duloxetlne or its
pharmaceutically acceptable salts comprises the steps of;
(a) Heck's coupling of 2-bromo thiophene with N-methyl allyl amine in presence of a base and a catalyst to obtain intermediate V which is reduced with Pd/C to obtain compound VIII followed by benzylic hydroxylation to yield compound IX;
(b) Resolving compound IX with L (+) tartaric acid to give compound X;
(c) O-arylating compound X in presence of catalyst such as trifluoroacetic acid with 1-naphthol to yield duloxetine.
5. The process as claimed in claim I, wherein preparation of duloxetine or its
pharmaceutically acceptable salts comprises the steps of;
(a) Heck's coupling of 2-bromo thiophene with N-methyl allyl amine in presence of a base and a catalyst to obtain intermediate V followed by acetylation with a suitable acetylating agent to obtain compound of formula XII;
(b) Michael addition of 1-naphthol in presence of trifluoro acetic acid and hydrocarbon solvent to obtain compound XIII; and
(c) Hydrolyzing compound XIII in presence of base to obtain racemic duloxetine followed by resolution with L (+) tartaric acid.
6. The process as claimed in claims 1 to 5, wherein the catalyst for Heck's
coupling is selected from palladium acetate, palladium chloride dipalladium
tris (dibenzylidenelacetone) ("PdDBA"), palladium tetrakistriphenylphosphine
etc.
7. The process as claimed in claim 1 to 5, wherein the base for Heck's coupling
is selected from alkali metal carbonates such as sodium carbonate, potassium
carbonate.
8. The process as claimed in claim 4, wherein the benzylic hydroxylation is carried out with vanadium pentoxide.
9. The process as claimed in claim 1 to 5, wherein the catalyst used for Michael addition of 1-naphthol is selected from metallic copper or copper compound such as Cu2O, CuCI, CuCN, copper acetylacetonate, copper (II) tetrafluoroborate etc. in polar solvents such as lower alcohols, ethyl acetate, acetone, etc.

10. A novel process for the preparation of duloxetine or its pharmaceutically
acceptable salts comprising the steps of;
(a) Prins reaction of 2-vinyl thiophene with Mannich adduct in presence of 1-naphthol to obtain racemic duloxetine; and
(b) Resolving racemic duloxetine with L (+) tartaric acid.

11. A novel process for the preparation of duloxetine or its pharmaceutically acceptable salts comprising Mannich reaction of methylamine -tartaric acid salt, paraformaldehyde and 2-acetyl thiophene to obtain compound XIV and reacting with 1-napthol to yield duloxetine.
12. The process as claimed in claim 9, wherein the Mannich adduct is obtained from reaction of methylamine hydrochloride and paraformaldehyde.
13. A novel intermediate of Formula IV;

14. A novel intermediate of Formula VII;

15. A novel intermediate of Formula V;

16. A novel intermediate of Formula XII;


17. A novel intermediate of Formula XIII;